Chemotherapeutic agents currently used for antitumor therapy are selected for their toxicity towards rapidly proliferating cells. Most of them cause undesirable systemic effects such as cardiac or renal toxicity, marrow aplasia, alopecia, nausea and vomiting. During the last few years, many authors have tried to eliminate these side effects by developing drugs having suitable physico-chemical properties allowing an increase of the availability of the drug to the tumors site. New molecules extracted from natural sources, synthetically or semi-synthetically produced, enzymes, radioisotopes, DNA toxins, various macromolecules, and antibodies against fibrin or against tumor-specific surface antigens are bound to drugs in an attempt to increase selectivity of the chemotherapeutic agents.
It is recognized that the ideal antineoplastic or anticancer drug would destroy cancer cells without adverse effects or toxicities on normal cells, but such drug has yet to be discovered. However, despite the narrow therapeutic index of many drugs, treatment and even cure are possible in some patients.
Chlorambucil and carmustine are commonly used antineoplastic agents from respectively the class of nitrogen mustards and nitrosoureas. They can be administered orally or intravenously, but these drugs cause nausea, vomiting, alopecia, lymphopenia, leucopenia and bone marrow depression. Their biological half-life is short (approximately 1-1.5 h) with a high percentage bound to plasma proteins (over 90%). Both nitrogen mustard and nitrosourea derivatives are extensively metabolized, yielding active and inactive metabolites.
Nitrogen mustard and nitrosourea derivatives are particularly effective in treating Hodgkin's disease and non-Hodgkin's lymphomas. In fact, they are among the most active synthetic molecules ever synthesized. Indeed, chlorambucil is used at doses up to 6 mg/m.sup.2 and carmustine is active in primary brain tumors because it crosses easily the blood brain barrier at low doses.
In J. Med. Chem., 1966, 9, 892-910, Johnston et al. discloses several N-nitrosoureas as potential anti-cancer agents. Corresponding urea derivatives were mainly used as intermediates for the synthesis of the nitrosoureas. Among the urea derivatives tested in vitro, non of them showed activity. Other examples of antitumor agents of the same family are disclosed in Clinical and Invest. Med, 1985, 49 (Gaudreault et al.); J. Pharm. Science; 1988, 77, 185 (Gaudreault et al.); Anticancer Research, 1988) 8, 595 (Gaudreault et al.); and J. Med Chem, 1963, 6, 669 (Johnston et al).
The effectiveness of most anticancer agents is greatly reduced because of their high toxicity and the nature of the illness. It is believed that the problem of high toxicity of the anticancer agents can be circumvented by chemical modifications of those structures in such a way that they act more specifically on tumor cells without increasing systemic toxicity.
The research in this field is therefore mainly directed to the synthesis of anticancer agents which would possess high antineoplastic activity, low systemic toxicity and low mutagenicity on normal cells. Preferably, such anticancer agents would possess an extended shelf life without experiencing polymerization or decomposition problems, and could be handled by anyone having minimal knowledge of this subject. Finally, such anticancer agents would be prepared easily in large quantities.